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Biomedical subjects

W Bodmer

Publications and source records attributed to W Bodmer.

At least 19 recordsLinked to original sources
PubMed2006

Altered CD45 expression in C77G carriers influences immune function and outcome of hepatitis C infection.

BACKGROUND: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. OBJECTIVE: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. RESULTS: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. CONCLUSIONS: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.

Animals↗
PubMed2002

Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas.

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

Adenoma↗
PubMed2000

Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q.

Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11. 17, 95% CI = 2.30-54.3, p < 0.001), accounting for approximately 4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for approximately 10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.

Adenoma↗
PubMed2000

APC mutations are sufficient for the growth of early colorectal adenomas.

It is not clear whether APC mutations are sufficient for early colorectal adenomas to grow or whether additional mutations at other loci are required. We previously have screened 210 early colorectal adenomas from familial adenomatous polyposis patients for mutations and allelic loss at APC. Here, we determined whether allelic loss at APC had any effect on the nearby alpha-catenin gene. However, loss on 5q in familial adenomatous polyposis adenomas rarely extended as far as alpha-catenin, and no differences in alpha-catenin protein expression were found in tumors that showed loss encompassing both APC and alpha-catenin. We then screened all 210 tumors for mutations at candidate loci other than APC (K-ras, beta-catenin, and allelic loss at 1p33-p35 and 1p36) and for microsatellite instability (MSI). Each of these loci has been implicated previously in early colorectal tumorigenesis. One tumor harbored a beta-catenin mutation and another MSI, but none showed K-ras mutation or allelic loss at 1p33-p35 or 1p36. These data support the following hypotheses derived from sporadic colorectal tumors: beta-catenin mutations are generally an alternative to mutations at APC, MSI is not usually an early phenomenon in colorectal tumorigenesis, and K-ras mutations are more typical of large- and moderate-sized adenomas. Contrary to some previous reports, chromosome 1p allelic loss is infrequent in very early adenomas. APC mutations are generally sufficient for colorectal tumors to grow to about 1-cm diameter, although chance mutations at other loci can provide these early colorectal adenomas with a selective advantage, and some colorectal tumors may develop along a pathway not involving APC.

Adenoma↗
PubMed1999

The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis.

APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.

Adenoma↗
PubMed1999

Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas.

Germline mutations in the LKB1/STK11 gene cause characteristic hamartomas and freckling to develop in patients with Peutz-Jeghers syndrome (PJS). The hamartomas arise as a result of somatic "second hits" at LKB1/STK11 and therefore contain a neoplastic element. The origin of the pigmented lesions in PJS is unknown and difficult to test, as these are hardly ever biopsied. PJS patients are at increased risk of benign and malignant tumors, particularly of the colon, breast, pancreas, testis, and ovary, although the increased risk for any one of these sites may be quite modest. Somatic LKB1/STK11 mutations have been found, albeit at a low frequency, in sporadic tumors of the colon, stomach, ovary, and testis. Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actually small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selective advantage to related malignant tumors, such as melanomas. We have therefore screened 16 melanoma cell lines, 15 primary melanomas, and 19 metastases for LKB1/STK11 mutations. Two LKB1/STK11 mutations were found: a missense change (Y49D) accompanied by allele loss in a cell line; and a missense change (G135R), without a detected mutation in the other allele, in a primary tumor. Both these mutations are highly likely to be pathogenic. Novel polymorphisms, including an unusual heptanucleotide repeat, were also found in introns 2 and 3. LKB1/STK11 mutations occur in a significant minority of tumors of several sites, including malignant melanomas.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.

BACKGROUND AND AIMS: Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evidence for the importance of the TGFbeta signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1. METHODS: SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS: No mutations were found in any of these genes. A G-A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS: It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.

Adenomatous Polyposis Coli↗
PubMed1998

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.

Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz-Jeghers syndrome (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p. We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1, has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1, and weaker similarity to many other protein kinases. Peutz-Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer.

Patterns of allele loss (loss of heterozygosity, LOH) have been studied in order to investigate the genetic pathways involved in the pathogenesis of three types of colorectal cancer (CRC): sporadic CRC without replication errors (RER-) (32 cases); sporadic RER+ CRC (23 cases); and ulcerative colitis-associated CRC (UCACRC) (16 cases). Each tumour was assessed for allele loss at ten microsatellite markers which map close to known or putative tumour-suppressor genes: APC (5q21-q22); DCC (18q21.1); 1p35-p36; p16 (9p21); 22q; 8p; E-cadherin (16q22.1); beta-catenin (3p22-p21.3); RB1 (13q14.1-q14.2); and HLA. Overall, high frequencies of allele loss (> 30 per cent) were found near DCC (42 per cent), p16 (38 per cent), 22q (37 per cent), 1p35-p36 (34 per cent) and APC (31 per cent), and low frequencies (< 20 per cent) near RB1 (16 per cent) and E-cadherin (13 per cent). LOH near beta-catenin, HLA, and on 8p occurred at frequencies between 20 and 30 per cent. The overall frequency of allele loss did not differ among the three tumour groups, but some variation was seen at individual loci. There was a significantly higher frequency of LOH at 1p35-36 in RER+ tumours compared to RER- tumours. Allele loss at this site was also associated with a more advanced Dukes' stage at presentation. In addition, RER- tumours showed a higher frequency of allele loss at p16 than RER+ tumours. No significant difference existed at any locus between the frequency of LOH in sporadic CRC and in UCACRC. Pairwise analysis showed a negative association between LOH at APC and DCC, and between LOH at chromosome 22p and p53 overexpression. Thus, there may be specific differences between the mutation spectra of RER+ and RER- CRCs, but there are large degrees of overlap among the underlying genetic pathways of these cancers and UCACRCs.

Adult↗
PubMed1998

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

DNA-Binding Proteins↗
PubMed1998

Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3.

A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Chromosomes, Human, Pair 19↗
PubMed1997

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.

Many human cancer susceptibility genes have been successfully mapped by genetic linkage studies. One that has so far eluded researchers is that for Peutz-Jeghers (P-J) syndrome, a condition characterized by intestinal hamartomatous polyposis and melanin spots of the lips, buccal mucosa and digits. A dramatically elevated risk of malignancy has also been documented. Gastrointestinal tumours as well as cancers of the breast, ovary, testis and uterine cervix appear to be overrepresented in families with this syndrome. The nature of hamartomatous polyps is equivicol. Hamartomas are usually considered histologically benign, but in the case of Peutz-Jeghers patients, there are reports of adenomatous and malignant changes in the polyps, and the possibility of a hamartoma-carcinoma sequence has been discussed. A search for a putative tumour suppressor locus was made using comparative genomic hybridization (CGH) of Peutz-Jeghers polyps, combined with loss of heterozygosity (LOH) study. Genetic linkage analysis in 12 families using markers from a deletion site demonstrated the presence of a high-penetrance locus in distal 19p with a multipoint lod score of 7.00 at marker D19S886 without evidence of genetic heterogeneity. The study demonstrates the power of CGH combined with LOH analysis in identifying putative tumour suppressor loci, and provides molecular evidence of malignant potential in hamartomas.

Adenocarcinoma↗